Age-related disease is arguably the single greatest challenge for biomedicine in the 21st Century. Age is the largest single risk factor for a panoply of diseases, including cardiovascular dysfunction, cancer, type II diabetes, osteoporosis, and neurodegeneration. Postponing (or decreasing the rate of) aging would retard the course of multiple age-related diseases and therefore substantially increase average health-span. Our ability to develop rational approaches to preventing or intervening in aging depends crucially on a thorough understanding of the basic mechanisms that cause aging, as well as the etiology of specific agerelated diseases. We believe that it is especially in this area of biomedicine where an interdisciplinary approach will accelerate discoveries and provide rational avenues for therapeutic intervention. In the long term this will lead to the establishment of a comprehensive new discipline, that of "Geroscience." Despite having identified 100s of genes that determine lifespan in simple organisms, we have no true understanding of how these genes are impacting on aging and disease. This is in part that most studies are carried in isolation by either looking at the basic biology of aging or separately at the impact of these identified genes on disease. In this proposal, which is directly relevant to Specfic Aim 1 of the U54, Specific Aim 1. To establish an interdisciplinary research program on the aging-disease relationship with a focus on neurodegeneration and cancer, we will address across three neurodegenerative disease models, Huntington's disease-Dr. Ellerby (Component 7), Dr. Hughes (Component 6), Dr. Nicholls and Gibson (Component 11), Parkinson's disease-Dr. Andersen (Component 9) and Alzheimer's disease-Dr. Bredesen (Component 1), and the model organism C. elegans-Dr. Kapahi (Component 2)- the role of histone deacetylase (HDACs) in neurodegeneration and aging. This represents a significant area as researchers have made a series of important discoveries in recent years on neurodegenerative disease and in aging that these enzymes (HDACs) play a major in role in neurodegeneration or aging. However, researchers have not yet dissected out in mammalian systems which family members are critical to target to prevent neurodegeneration and aging. A central theme of these projects is the notion that genes that are known to modulate aging are key factors in determining disease. Drugs that target the maintenance functions of these regulators or enhance their function will be important targets for proposed interventions. Our hypothesis is that compromised acetylation homoeostasis is directed coupled to neurodegeneration and identification of particular HDACs family members involved in this process will identify therapeutic targets critical to neurodegeneration and aging.